The goal of this Phase I is to develop a prototype for a novel antiviral therapy directed towards Epstein-Barr virus based on a novel post-transcriptional regulatory mechanism called structurally interacting RNA or sxRNA. We are pioneering a revolutionary antiviral approach that uses a viral-encoded microRNA (miRNA) to create specificity even in infections in their latent stage. This transient mRNA therapeutic will make it possible to specifically express a protein of interest only in virus-infected cells by exploiting post-transcriptional regulation of a transgene triggered by the unique miRNA profile of a virus-infected cell. We have developed a trans-RNA switching mechanism called structurally interacting RNA or sxRNA for short that relies on the unique expression of a microRNA to turn on and off the expression of an ectopic gene of choice. Certain RNA binding proteins (RBPs) when bound to mRNA increase translation by several orders of magnitude. We have shown that it is possible to create a switch within an mRNA such that a trans-interaction with an endogenous miRNA can ablate or stabilize an RBP binding site. By coupling this post-transcriptional gene regulation with the microRNA signature patterns in cell types, sxRNA technology can enable cell specific expression of a desired protein or reporter gene to positively or negatively select for a tissue type, disease state or developmental stage. sxRNA technology represents a revolutionary way to regulate transient gene expression based on the unique miRNA profile in a cell. We propose to develop a novel sxRNA-based anti-viral directed against Epstein-Barr virus (EBV), an oncovirus. In addition to causing infectious mononucleosis, EBV is associated with cancers of B cells (e.g. immunocompromised-associated B-cell lymphomas including Burkitt and Hodgkin lymphomas) and epithelial cells (e.g. nasopharyngeal cell carcinoma, gastric carcinoma and breast cancer). A therapeutic that targets both lytic and latent EBV would make a significant impact on human health, and lead to similar therapeutics to other members of the Herpesvirus family.